The management of children with pediatric mastocytosis poses a challenge. There is a limited information as to the application of clinical and laboratory findings and bone marrow evaluation as they relate to medical intervention and prognosis. The diagnostic criteria for pediatric mastocytosis are largely based on adult studies. There is very little data about bone marrow pathology in children with mastocytosis. We evaluated the use of the World Health Organization (WHO) criteria for the diagnosis of systemic disease in pediatric patients. Bone marrow biopsies were analyzed by histopathology and immunohistochemistry, flow cytometry and KIT mutational analysis. Complete bone marrow evaluations were performed in 50 cases. Seven children had repeat procedures. We identified unique clinico-histopathological features within the biopsies. Bone marrow biopsies displayed mildly atypical hematopoietic maturation, increased hematogones and hypocellularity in a sub-set of patients with urticaria pigmentosa, diffuse cutaneous mastocytosis and indolent systemic mastocytosis. Hypocellularity was most pronounced in those with urticaria pigmentosa. Hematogone increases were highest, on average, in patients with diffuse cutaneous mastocytosis or mastocytomas. There was no evidence of peripheral blood cytopenias, myelodysplastic syndrome, myeloproliferative neoplasm or leukaemia within this cohort. Long-term follow-up of patients within this study (median 6.9 years; range 1-25 years) showed that all patients remained clinically stable without progression to a more aggressive variant. We conclude that the WHO criteria are applicable for the diagnosis of systemic mastocytosis in pediatrics. In a related study, we sought to examine clinical aspects of pediatric mastocytosis in relationship to serum tryptase levels and bone marrow histopathology to provide practical clinical guidance for management of this rare group of patients. 105 children were evaluated at our institution over the span of 25 years. Baseline tryptase levels and at least 1 subsequent tryptase measurement were available in 84 and 37 of these children, respectively. Fifty-three children underwent a bone marrow examination. Organomegaly was confirmed by means of ultrasound in all cases. In a cohort of patients with high tryptase levels and severe mediator symptoms, organomegaly was a strong indicator of systemic disease. All patients with organomegaly had systemic mastocytosis disease, while none without organomegaly had systemic disease. Serum tryptase levels differed significantly between patients with urticaria pigmentosa and those with diffuse cutaneous disease (P < .0001) and systemic mastocytosis (P < .0001) and in all 3 categories versus control subjects (P < .0001). Tryptase levels and symptoms decreased over time in most patients. Tryptase levels correlated with bone marrow mast cell burden in patients with systemic mastocytosis (P < .0001). There was a significant relationship between clinical resolution and the percentage decrease in tryptase levels (P = .0014). The majority of children (57%) experienced major or complete disease resolution during the follow-up period, whereas the remainder exhibited partial improvement. Serum tryptase levels furthered classification and reflected clinicopathologic findings, while sequential tryptase measurements were useful in supplementing clinical judgment as to disease course.